Clinicopathologic and 11C-Pittsburgh Compound B Implications of Thal Amyloid Phase Across the Alzheimer's Disease Spectrum

Brain. 2015 May;138(Pt 5):1370-81. doi: 10.1093/brain/awv050. Epub 2015 Mar 23.

Abstract

Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Keywords: Alzheimer’s disease; Braak tangle stage; Pittsburgh compound B; Thal amyloid phase; neuropathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / pathology*
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Aniline Compounds*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Plaque, Amyloid / pathology*
  • Positron-Emission Tomography / methods
  • Thiazoles*

Substances

  • 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
  • Amyloid
  • Amyloid beta-Peptides
  • Aniline Compounds
  • Thiazoles